While some proteins have a mainly structural role in cellular life, many proteins are biologically active. Living cells include many mechanisms by which the biological activity of a protein is modulated, including: modification of concentration of the protein or its substrates, modification of the concentration of materials that catalyzes protein activity, indirect modification of protein structure, such as by changing of pH or concentrations of materials that modify protein structure, and direct modification of protein spatial structure and/or charge distribution by attachment of cofactors such as a phosphate moiety (phosphorylation), glucose, ions, metal ions, heme groups or iron-sulfur complexes and coenzymes for example.
The symptoms of many diseases include changes in protein activity, as indicated, for example, by phosphorylation (hyper- or hypo-). One example is cardiac heart failure, where, as the disease progresses the phosphorylation of some proteins goes down and others go up. Levels of various proteins also change.
As described, for example in N Engl J Med 346:1357, 2002, the disclosure of which is incorporated herein by reference, patients with CHF who respond to therapy with beta blockers manifest reversal that is normalization of the maladaptive fetal gene program.
In a paper entitled “Voltage-dependent potentiation of the activity of cardiac L-type calcium channel al subunits due to phosphorylation by cAMP-dependent protein kinese”, by Adrian SCULPTOREANU, Eric ROTMAN, Masami TAKAHASHI, Todd SCHEUER, AND William A. CATTERALL, in Proc. Natl. Acad. Sci. USA Vol. 90, pp. 10135-10139, November 1993 (Physiology), the disclosure of which is incorporated herein by reference, fast phosphorylation of trans-membrane calcium channels and a possible mechanism therefore, are described.
U.S. Pat. No. 6,919,205, the disclosure of which is incorporated herein by reference, describes regulation of type II cartilage genes and proteins using electromagnetic and electric fields.
PCT publication WO 2005/056111, the disclosure of which is incorporated herein by reference describes using a PMF signal on calcium dependent myosin phosphorylation in a cell free reaction mixture.
PCT publication WO 2005/102188, the disclosure of which is incorporated herein by reference, describes PMF stimulation applied to Jurkat cells reduces DNA synthesis and makes them behave like normal T-lymphocytes stimulated by antigens at the T-cell receptor such as anti-CD3, possibly by interacting with the T-cell receptor.
PCT publication WO 2005/105013, the disclosure of which is incorporated herein by reference, describes applying a PMF to a heart in order to achieve angiogenesis and neovascularization.
Dhein (2006; Adv Cardiol. 42:161-74) describes a remodeling process which changes the electrophysiology of the cells and the gap junctional communication within the tissue as a result of atrial fibrillation. Dhein concludes that Gap junctions contribute to the initiation of atrial fibrillation within the pulmonary veins as well as to the stabilization of fibrillation by providing a network of cells enabling multiple wavelets. Dhein specifically observed changes in the expression levels of Connexin proteins (Cx43 and Cx40). The contents of this article are fully incorporated herein by reference.
Gollob (2006; Curr Opin Cardiol. 21(3):155-8) reports that animal models deficient in cardiac connexins demonstrate abnormalities in myocardial tissue conduction and vulnerability to re-entrant arrhythmias, including ventricular tachycardia and atrial fibrillation. Gollob notes that atrial tissue analyses from human patients with atrial fibrillation consistently demonstrate alterations in connexin distribution and protein levels and postulates a role of connexins in the perpetuation of the arrhythmia. In addition, Gollob notes that genetic studies of Cx43 and Cx40 indicate that genetic variations in these genes may predispose to arrhythmia vulnerability in humans. The contents of this article are fully incorporated herein by reference.
Walker and Rosenbaum (2003; Cardiovasc Res. 57(3):599-614) report that T wave alternans hastens ventricular tachyarrhythmias in a wide variety of clinical and experimental conditions. They suggest that alternans is linked to the kinetics of intracellular calcium cycling and that alternans is linked directly to the pathogenesis of arrhythmias. Because a T wave alternans is closely related to a mechanism of arrhythmogenesis, it seems a strong marker of clinical risk of arrhythmia. The contents of this article are fully incorporated herein by reference.
Wilson et al. (2006; Ann N Y Acad Sci. 1080:216-34) suggest that studies in normal hearts establish a link between impaired calcium cycling which characterizes ventricular mechanical dysfunction and impaired calcium cycling that is responsible for T wave alternans. They note that in normal myocardium, cells which exhibit the slowest calcium cycling, and not the slowest repolarization, are most susceptible to alternans and that decreased expression of key calcium cycling proteins is observed in alternans-prone cells. For example, sarcoplasmic reticulum ATPase (SERCA2a) expression is decreased, suggesting a mechanism for the slower sarcoplasmic reticulum (SR) calcium reuptake observed in alternans-prone cells. In addition, diminished ryanodine receptor (RyR) function leading to abnormal calcium release from the SR is also linked to cellular alternans. They propose that cellular calcium alternans may be an important mechanism linking mechanical dysfunction to cardiac arrhythmogenesis. The contents of this article are fully incorporated herein by reference.